Abuse of and dependence on opioid drugs are highly significant problems for our nation and the world. Persons addicted to opioid drugs suffer from numerous health and social problems which cause them to become a major burden on government and society at large. Massive amounts of capital and human resources are expended yearly in attempts to treat and support addicted individuals and their families, to interdict the flow of illicit, impure, and unsafe opioids (and other drugs) into the nation, and to combat the criminal behavior resulting from dependent persons' need to support their drug use habits. In contrast to the magnitude of this problem, our understanding of the pharmacologic processes leading to drug tolerance and dependence remains unacceptably limited. The broad objective of this proposed research is to develop qualitative and quantitative models, which use practically obtainable, scientifically accepted parameters describing the magnitude and duration of drug action, to predict the liability of individual, currently available opioid drugs to cause tolerance. The ultimate utility of such models will lie in their ability to predict tolerance-inducing ability for novel opioid drugs which have been studied only in the laboratory environment and tested on a relatively small number of animal subjects, thereby guiding the development of new, safe analgesics and other therapeutic agents. The experimental methodology employed to achieve this objective will be a synthesis of techniques used in several different disciplines, particularly classical pharmacology, analytical chemistry, and pharmacokinetics. Animal experiments will be conducted using small rodents, primarily rats, and will involve both in vitro studies using animal tissue, and studies in intact rats involving the administration of opioid drugs, blood sampling for the determination of drug pharmacokinetics, and simultaneous measurement of drug effects on pain sensation. Computerized analysis and modeling of simultaneously obtained drug concentration and effect data will be used extensively so that maximum information, is obtained from as few animal subjects as possible. Finally, incorporation of specific drug/receptor interaction parameters, obtained from in vitro studies, into these drug concentration/effect models will permit the assessment of the relative importance of pharmacokinetic and pharmacodynamic drug properties in determining tolerance and dependence liability.